Cannabinoids are present in Cannbis sativa containing 100 kinds or more of C21 terpenophenol based compounds [Y. Gaoni R M., J. AM. Chem. Soc. 1964, 86(8): 1646-1647]. 9-thetrahydrocannabinol (THC), which is the best-known among them, binds to a cannabinoid receptor known as a G-protein-coupled receptor (GPCR) in a human body to cause a mental effect [Pertwee R G., Pharmacol. Ther. 1997, 74(2): 129-180]. After two different subtypes (CB1R and CB2R) of the cannabinoid receptors were found and cloned, research into a novel cannabinoid receptor antagonist has been promoted, such that various kinds of cannabinoid receptor antagonists have been developed. In addition, it was found that anandamide (AEA), 2-arachidonyl glycerol (2-AG), palmitoylethanolamide (PEA), and the like, which are endogenous cannabinoids binding to the cannabinoid receptor to act thereon, were present in the body [Pertwee R G., Pharmacol. Ther. 1997, 74, 129-180].
The cannabinoid receptor 1 (CB1R) was mainly expressed in a central nervous system, but recently, it was confirmed that the cannabinoid receptor 1 (CB1R) was also expressed in a peripheral nervous system and immune cells, and the cannabinoid receptor 2 (CB2R) was mainly expressed in an immune system such as B cells, T cells, macrophages, lymph nodes [Howlett A C, Barth F, Bonner T I, Cabral G, Casellas P, Devane W A, et al., Pharmacological Reviews 2002, 54(2): 161-202]. Particularly, it was found that both of the CB1R and CB2R were expressed in mast cells, a kind of immune cells, and the cannabinoid receptor antagonists may regulate an activity of the mast cells [Klein T W, Newton C, Friedman H., Immunology Today 1998, 19(8): 373-381].
It was known that activation of the mast cells was important for various allergy responses and inflammatory responses [Wasserman S I., J. Allergy Clin. Immunol. 1983; 72: 101-119]. The mast cells playing an important role in an innate immunity system regulate inflammatory responses and repair and remodeling of damaged tissue in addition to serving as a defense mechanism against infection [Stone K D, Prussin C, Metacalfe D D., J. Allergy Clin. Immunol. 2010, 125: S73-80]. The mast cells were immunologically activated by receptor cross-linking by immunoglobulin E (IgE) binding to high affinity IgE receptors, but a physiological regulation mechanism on cytokine release of the mast cells was not known yet. Recently, it was reported that endogenous cannabinoids may serve as autacoids inhibiting activation of mast cells and suppressing local inflammatory responses [Aloe L, Leon A, Levi-Montalcini R., Agents Actions 1993, 39: C145-C147]. Facci et al, initially reported in 1995 that CB2R, which is the cannabinoid receptor, was expressed in mast cells present in the peritoneum of a rat and RBL-2H3, which is a rat basophilic leukaemia cell line, and they confirmed that release of cytokines was suppressed in the mast cells by PEA, thereby asserting that activation of the CB2R suppress inflammation [Facci L, Dal Toso R, Romanello S, Buriani A, Skaper S D, Leon A., Proc. Natl. Acad. Sci. USA. 1995, 92: 3376-3380]. It was reported that in rats to which PEA was orally administered, formation of oedema was decreased, inflammatory hyperalgesia was also decreased, and a synthesized cannabinoid JWH133, which is known as a CB2R agonist decreases oedema by mast cells [Kent-Olov J, Emma P, Christopher J F., Life Sciences 2006, 78:598-606]. Meanwhile, roles of the CB1R in the mast cells were not well-known unlike the CB2R, but recently, research into the CB1R has been conducted. WIN 55,212-2, which was known as a selective CB1R agonist, suppresses release of b-hexosaminidase in RBL-2H3 mast cells [Giudice E D, Rinaldi L, Passarotto M, Facchinetti F, D'Arrigo A, Guiotto A et al., J. Leukoc. Biol. 2007, 81:1 512-1521].
Among skin diseases, atopic dermatitis is a representative disease of which symptoms are aggregated by excessive activation of the mast cells. Atopic dermatitis is a chronic recurrent skin disease, and the accurate causes of atopic dermatitis were not known, but it has been estimated that pathogenesis of atopic dermatitis was complicatedly associated with genetic, environmental, and immunologic factors [Morren M A, Przybilla B, Bamelis M, Heykants B, Reynaers A, Degreef H., J. Am. Acad. Dermatol., 1994, 31, 467˜473]. In patients with atopic dermatitis, the mast cells were activated in both an IgE-dependent response and an IgE-independent response, such that plasma membrane and cytoplasmic fine membrane are fused with each other, thereby causing degranulation. When various allergens bind to specific IgE of the mast cells or basophils, the allergen strongly binds to an IgE receptor FceRI on surfaces of the mast cells, such that proteoglycan, eicosanoid, protease, and TNF-a, IL-4, IL-6, IL-13, TGF-β, and the like, which are various chemotactic cytokines, as well as histamine are released [Jutel M, Akdis M, & Akdis C A., Clin. Exp. Allergy 2009, 39(12): 1786-1800]. Among them, histamine, which is a strong vasoactive mediator having the most diverse characteristics, expands the blood vessel to induce a larger number of immune cells so as to move to a lesion site.
A material capable of suppressing activities of the mast cells to decrease histamine released therefrom and decreasing vascular permeability may provide efficacy more suitable for treating and preventing atopic dermatitis than a general immunosuppressive material. A technology of preventing and alleviating atopic dermatitis and itching according to the related art is to administer anti-histamine or use steroids, but at the time of administration or application of these medicines, side effects such as the central nervous system disorder, digestive disorder, numbness state, or the like, occur. Therefore, the development of a novel material and agent which may overcome these side effects and do not have toxicity has been required.